1. Field of the Invention
This invention relates to a composition having antiviral activity for prophylaxis or treatment of positive-stranded RNA virus infection or a disease, and more particularly to the composition comprising flavonoid baicalein for prophylaxis or treatment of a flavivirus infection.
2. Description of Related Arts
The positive-stranded RNA virus including flavivirus family comprises many medically important viruses which include dengue, a serious mosquito-borne disease common in the tropics and sub-tropical regions of the world. Dengue has caused many deaths and afflicted millions of people annually and threatened almost 2.5 billion people living in the regions. It is amongst the most rapidly spreading mosquito-borne viral infection.
Dengue is caused by dengue virus a member of the genus flavivirus, family Flaviviridae, a positive-strand RNA virus. Other common medically important virus in this family includes Japanese encephalitis virus, Yellow fever virus, Hepatitis C virus, West Nile encephalitis virus, Murray Valley encephalitis virus, Tick-borne encephalitis virus, St. Louis encephalitis virus and Kyasanur Forest disease virus. Infection by any of these viruses results in a wide spectrum of clinical illnesses ranging from a silent asymptomatic or mild febrile infection, self-limited infection to the severe encephalitis, hepatitis and deaths. Similarly, dengue can manifests as self-limited dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). There are four serotypes or genotypes of dengue virus, dengue virus type-1 (DENV-1), dengue virus type-2 (DENV-2), dengue virus type-3 (DENV-3) and dengue virus type-4 (DENV-4) which are transmitted to human by at least two species of mosquitoes, Aedes agypti and Aedes albopictus. All four dengue virus genotypes cause similar clinical symptoms. The mechanisms of how one contracted severe dengue is still unknown. The severity of dengue is said to be directly correlated to the amount of virus present in a person's blood.
To date, there is no approved therapeutics or antiviral therapy for the treatment of most of the flavivirus infection if not all of them, including dengue. There is no effective antiviral that can help to reduce dengue virus load in patients to prevent the severe manifestation of dengue, DHF or DSS. Due to the rapidly expanding dengue disease globally, it is critical to develop an effective antiviral drugs or acceptable vaccines against dengue. Effort to prevent dengue using vaccine is plagued with many potential issues and risks. Therefore, an effective drug that can help to reduce dengue virus load during early stage of infection is much desired.
Plants and plant derived compounds remained an important source of new antiviral drugs due to their potential low side effects and their ubiquitous accessibility in nature. There have been a few reports on antiviral activities of various phytochemicals against dengue viruses. Among these include the flavonoids. Flavonoids are low molecular weight phenolic compounds found widely in different types of plants. Different types of flavonoids can be found in fruits, roots, nuts, seeds, bark, steams and flowers of plants. Baicalein (5,6,7-Trihydroxyflavone), which is a type of flavonoid, is found in the roots of a number of herbal plants.
Antiviral activities of baicalein have been evaluated against a number of common human viruses which include the double-stranded DNA viruses, herpesviruses and few negative-stranded respiratory viruses but none that demonstrate it as inhibitor of a positive-stranded RNA virus replication. The application of baicalein as an effective inhibitor of the positive-stranded RNA virus, more specifically the flavivirus, dengue virus replication is emphasized in the present invention.
US Patent Application Publication No. 2010/0004325 A1 disclosed a new molecular and cellular effect of baicalein, which is selected by a proxlylhydroxylase 2 (PHD2) inhibitor screening method using a compound library. The cited art analysed the hypoxia inducible factor (HIF) protein expression induced by baicalein in cells, quantitatively analyzed the inhibitory effect of baicalein against PHD2, confirmed the inhibitory effect against factor inhibiting HIF, and confirmed whether VEGF is expressed by using a reporter assay and ELISA. The cited art proved that baicalein can be used as a drug to treat ischemic disease, and other related diseases. Nonetheless, the cited art did not mention specific composition of baicalein that will work as inhibitor against flavivirus replication. Therefore, there is a need to have a certain workable composition or concentration of baicalein that exhibit antiviral property, particularly to dengue virus. Besides that, there is a need to maximise the potential of baicalein for reducing viral RNA replication in treating and preventing infectious diseases triggered by RNA viruses belonging to the genus of Flavivirus by having different concentrations of baicalein to exhibit direct virucidal activity, prophylactic property, and anti-attachment activity.
US Patent Application Publication No. 2008/0176932 A1 is an invention that relates to a pharmaceutical composition having synergistic anti-tumour effects, more specifically to a pharmaceutical composition comprising of flavonoids. The cited art further relates to the preparation and pharmaceutical use of the composition, which contains baicalein and baicalin or scutellarin. The cited prior art also disclosed compositions of baicalein and baicalin or scutellarin and its related compound that exhibit anti-tumour effects, but did not mention the composition on flavivirus replication. Therefore, there is a need to have a composition or a compound that exhibit antiviral property and inhibit flavivirus replication, particularly in dengue virus and Japanese encephalitis virus.
U.S. Pat. No. 6,083,921 relates to pharmaceutical compositions having antiviral, antibacterial, or immune modulating property in general and in particular to pharmaceutical compositions useful in the treatment or prevention of infection by parainfluenza or respiratory syncytial virus. The pharmaceutical compositions are obtained from combinations of plants containing baicalin, chlorogenic acid, and forsythiaside particularly in isolated and purified form. The pharmaceutical composition usefulness does not extend to positive stranded RNA viruses particularly flavivirus. Therefore, there is a need to resolve the cited prior art by having a composition consisting of baicalein as the active antiviral ingredient, to treat and prevent infection caused by the positive-stranded RNA virus such as the flavivirus, for example dengue virus and Japanese encephalitis virus.